Kidney is the main organ that produces erythropoietin, and erythropoietin is mainly produced in tubulointerstitial cells in the kidney.
Erythropoietin is a hormone consisting of 165 amino acids. Erythropoietin binds to a receptor on an erythroid progenitor cell in the hematopoietic tissue, and promotes the proliferation and differentiation of the erythroid progenitor cell. In this way, erythropoietin modulates the production of erythrocytes.
Under normal circumstances, the production of erythropoietin is regulated by oxygen partial pressure in the blood, thereby regulating the production of erythrocytes. When anemic, the kidney increases the production of erythropoietin in order to orient towards hematopoiesis, and as a result erythropoietin in the blood increases.
However, when the production of erythropoietin in the kidney is reduced due to kidney disorder etc., erythropoietin in the blood will not be increased even when anemic, and a pathological state is triggered where the production of erythrocytes is suppressed. Such a pathological state is renal anemia. In other words, renal anemia is an anemia arising mainly from the reduction of erythropoietin (EPO) production in the kidney due to kidney disorder etc. Among renal diseases, particularly in the case of a chronic renal disease, renal anemia does not necessarily occur because the decrease in renal function progresses gradually. However, in the case of an acute renal disease such as renal failure among renal diseases, it is known that renal anemia occurs at a high probability. In addition, numerous cases of anemia are seen which are caused by the reduction of erythropoietin production totally unrelated to the onset of renal disease. Thus, anemia arising from the reduction of erythropoietin including renal disease, in particular chronic renal disease does not have the same onset mechanism as renal anemia.
Examples of characteristic symptoms of renal anemia include shortness of breath, palpitation, dizziness, decreased appetite, and lassitude.
It is known that uremia also occurs in a patient with progressed renal failure. Uremia is a pathological state where waste products such as urea remain in the blood due to decrease in renal function. Uremic patients develop various symptoms, and the symptom of renal anemia is one of them.
ESA (erythrocyte hematopoietic stimulating factor preparation) has been developed and been put to practical application as a method for treating such renal anemia. Examples of ESA include (1) erythropoietin, (2) erythropoietin derivative, and (3) other compounds that stimulate erythropoietin receptor.
The therapeutic policy for renal anemia in Japan is implemented based on the following guidelines (Non-Patent Document 1).
1) ESA (erythrocyte hematopoietic stimulating factor preparation) therapy should be initiated when diagnosis of renal anemia is confirmed and administration criteria are satisfied (active recommendation).
2) Administration of iron preparation necessary for hematopoiesis should be used in combination (active recommendation).
3) Make effort to clean the dialysate and perform sufficient dialysis in maintenance hemodialysis (HD) patients (active recommendation).
4) In patients with nutrient disorder or inflammation, active therapy against these should be performed (active recommendation).
As shown in the above guidelines, ESA is recommended as the first-line drug for renal anemia therapeutic agent in Japan.
However, it is known that some renal anemia patients show resistance to ESA therapy. There are still many unclear points regarding the mechanism of why the reactivity produced towards ESA therapy is low. As one of the reasons for such low reactivity towards ESA therapy, increase in blood concentration of inflammatory cytokines such as TNF-α and IL-6 is thought to be an active reason. Inflammatory cytokine is a causative factor that causes various inflammation symptoms in vivo. Inflammatory cytokine is also known to shorten the lifespan of erythrocytes. Inflammatory cytokine is also known to reduce the production of erythropoietin by erythropoietin producer cells. Accordingly, inflammatory cytokine is thought to be a causative substance that causes anemia.
ESA therapy also has the risk of causing thrombosis or myocardial infarction etc. as its side effect. Poor prognosis of malignant tumors has also been reported recently.
As stated above, ESA therapy is merely a palliative therapy, and does not possess an action to restore the reduction of erythropoietin production by erythropoietin producer cells.
There was further a problem regarding compliance since oral administration of ESA is typically difficult.